Use of SGLT2 Inhibitors vs GLP-1 RAs and Anemia in Patients With Diabetes and CKD

Key Points Question Is the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors associated with reduced risk of anemia in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) stages 1 to 3? Findings In this cohort study with 13 799 participants, initiation of SGLT2 inhibitors was associated with a 19% decrease in incident anemia risk compared with initiation of glucagon-like peptide-1 receptor agonists. Changes in hemoglobin, hematocrit, and red blood cell counts during the follow-up period supported this observation. Meaning The study findings suggest potential benefits for anemia incidence after SGLT2 inhibitor initiation in patients with T2D and CKD.

Co-medications only included drugs that were prescribed 84 days before the index date.Same as target trial.

Study design
Open-labelled, pragmatic clinical trial.
Same as target trial.
2. HbA1c levels more than 6.5% in the baseline period.
Same as target trial.12. History of human immunodeficiency virus.[CREDENCE: 2. HbA1c levels more than 6.5% in the baseline period. [CREDENCE: #2] [CREDENCE: #6] b: These criteria are standard requirements in conducting clinical trials, but they were not applicable in the observational study.
c: All procedural criteria were condensed into 'hospitalization record with a blood transfusion history within 12 weeks before the index date' with stricter criteria specifically tailored to our study outcomes.

d:
As there was no direct NYHA stage classification in the database, severe heart failure was redefined as 'clinical diagnosis of hospitalizations for heart failure at discharge and BNP levels > 400 pg/ml' during the baseline period.
e: According to our reimbursement regulations, the combination use of ACE inhibitors and ARBs is contraindicated and not permitted in our reimbursement plan.
Therefore, the combination of these two medications will not occur.1. Patients who had a history of diabetic ketoacidosis or type 1 diabetes mellitus.
2. Patients with a history of non-diabetic kidney diseases, such as hereditary glucose-galactose malabsorption or primary renal glucosuria.
3. Patients with a history of hereditary nephropathy or primary nephrotic syndrome.
4. Patients with a history of renal transplant by at least two coding records.
5. Patients with hyperkalemia, i.e., blood potassium levels exceeding 5.5 mmol/l twice within the year preceding the index date.
6. Patients with uncontrolled hypertension, defined as systolic blood pressure exceeding 180 mmHg or diastolic blood pressure exceeding 100 mmHg, recorded twice within the year preceding the index date.
7. Patients with a clinical diagnosis of severe heart failure, defined as hospitalization for heart failure at discharge with B-type natriuretic peptide levels higher than 400 ρg/ml, within one year before the index date.
8. Patients with elevated liver enzymes, with either alanine transaminase levels more than 2.0 times the upper limit normal (50 U/l in males; 35 U/l in females) or total bilirubin more than 1.5 times the upper limit normal (1.2 mg/dl), twice in the last two results within one year before the index date.
9. Patients with a clinical diagnosis of significant liver disease (including hepatic failure, chronic hepatitis, fibrosis and liver cirrhosis) within one year before the index date.
10. Patients who had a clinical diagnosis of malignancy within one year before the index date.
11. Patients with a history of human immunodeficiency virus.
12. Patients with a history of atraumatic amputation.
13. Patients who underwent major surgery (defined as hospitalization record with red blood cell transfusion history) within 12 weeks before the index date.
14. Patients who had a clinical diagnosis of osteomyelitis or peripheral arterial occlusion disease within six months of the baseline period.
15. Pregnant or breastfeeding women within one year before the index date.
doi:10.1001/jamanetworkopen.2024.0946eFigure 1. Study design diagram eFigure 2. Propensity score distributions eFigure 3. Survival curves for composite anemia outcomes over time (in days) eTable 1. Target trial emulation design framework eTable 2. Comparison of eligibility criteria for the CREDENCE and DAPA-CKD trials, and this proposed study eTable 3. Details of exclusion criteria eTable 4. Disease diagnosis codes for the exclusion criteria eTable 5. Disease diagnosis codes to identify baseline comorbidities eTable 6. ATC codes to identify co-medications eTable 7. ATC codes to identify exposure or comparator drugs eTable 8. Composite anemia outcome definitions eTable 9. Individual effects of each SGLT2 inhibitor with regard to composite anemia outcomes eTable 10.Sensitivity analysis of composite anemia outcomes This supplemental material has been provided by the authors to give readers additional information about their work.eFigure 1. Study design diagram CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate; GLP-1 Abbreviations: GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; SGLT2: Sodium-glucose cotransporter-2

eTable 2 .
Comparison of eligibility criteria for the CREDENCE and DAPA- The criterion of 'Stable maximum tolerated labeled daily dose of ACE inhibitor or ARB' was removed in the presented target trial emulation study because the CREDENCE and DAPA-CKD trials aimed to assess the effects of SGLT2 inhibitors on renal outcomes in participants at high risk of CKD progression.In addition, underuse of these medications in patients with T2DM in clinical practice has been reported.